DESCRIPTION: (Applicant's Description) The objective of this proposal is to apply the controlled release technology to optimize the efficacy of radiotherapy by local and sustained delivery of radio-seeds arid radiosensitizers. The hypothesis as outlined in Project 1 is that protracted irradiation can be a potent radiosensitizer, particularly of radio-resistant tumor cells. The hypothesis as outlined in Project 1 is that protracted irradiation can be a potent radiosensitizer, particular of radio-resistant tumor cells. When delivered by brachytherapy or by external beam, protracted irradiation sensitizers xenograft tumors to external beam fractionated radiotherapy. We will develop a delivery system based on biodegradable polymeric microspheres and viscous gel to effect the desired spatial and temporal distribution patterns of radionuclides in tumor tissue. This will allow the efficacy of combination of drug arid radio-therapy, particularly combined fractionated high dose rate external bean irradiation and continuous low dose rate irradiation to be optimized. While Project 1 defines the underlying mechanisms that determine the response of tumor cells to acute and protracted irradiation, we will develop a platform delivery technology to achieve optimal irradiation pattern based on their findings. The specific aims are: (1) To develop immunomicrospheres for delivery of radionuclides and radiosensitizers through intra-tumoral injection. The biodegradable microspheres will be synthesized based on complex coacervation of gelatin and chondroitin sulfate for the controlled delivery of IUdR and other potential radiochemicals. We will initially aim at formulations with microsphere degradation times of two months and one week. The more stable formulation will be for prolonged delivery of a therapeutic dose of I-125 or I-131, which has a half-life of 56 days, to the tumor tissue. The faster degrading micro spheres would target fast growing tumors and facilitate study of tumor response to external beam irradiation. The microspheres will be well characterized with respect to size, size distribution, drug loading level, and in vitro release kinetics. The different microspheres will be optimized based on feedback of mechanistic studies conducted in Project 1 and the biodistribution and tumor regrowth studies conducted in Core B. (2) To synthesize liposomes containing I-125 or I-131 labeled IgG and IgM fragments or IUdR for comparison with the polymeric controlled delivery systems. The liposomes will be prepared by the well-established procedures consisting of hydration and extrusion. They will by characterized with respect to size, size distribution, zeta potential, drug loading level, and in vitro release kinetics. Biodistribution studies in xenografts will be conducted in comparison with radioseeds, the immunomicrospheres, free I-31 labeled IgG and IgM fragments, and free IudR. (3) To develop a carrier for sustained delivery of radionuclides t the tumor tissue by fluid injection. We will synthesize a novel biodegradable polyphosphate viscous gel with properties that balance ease of injection with desired degradation kinetics. Composition of the backbone of the polymer will be systematically varied with respect to the co-monomer ration of hydrophobic and hydrophilic diols. The parameters to be optimized are ease of injection and distribution volume in the tumor tissue, which is related to the viscosity of the gel, and the rate of release and of polymer degradation. Two approaches, encapsulation and covalent conjugation, will be adopted to adjust and maximize retention of the radionuclides in the tumor tissue.